Lipoprotein(a) (Lp(a)) is a genetically determined, proatherogenic lipoprotein linked to increased cardiovascular risk. Although elevated Lp(a) levels have been implicated in peripheral artery disease (PAD) development, their prognostic significance in patients with established PAD remains unclear. To evaluate whether elevated Lp(a) independently predicts short-term cardiovascular and limb outcomes in patients with established PAD. Using the TriNetX Research Network, we conducted a retrospective cohort study of adults with PAD between January 1, 2010, and January 1, 2025. Patients with Lp(a) measurements were stratified by Lp(a) levels (≥50 mg/dL vs <50 mg/dL). A 1:1 propensity score matching (PSM) controlled for demographics and cardiovascular comorbidities. Primary outcomes included 1-year rates of myocardial infarction, stroke, major adverse cardiovascular events (MACE), all-cause mortality, and major adverse limb events (MALE). Among 1,790,984 PAD patients, 3,397 (0.2%) had elevated Lp(a). After PSM, 2 balanced cohorts of 3,397 patients were analyzed. In the unmatched cohort, elevated Lp(a) was associated with higher rates of myocardial infarction, stroke, and MACE, but paradoxically lower all-cause mortality and major adverse limb events (MALE). However, in the matched cohort, these differences were no longer statistically significant, suggesting the initial findings were likely driven by baseline differences and confounding. In patients with established PAD, elevated Lp(a) was not independently associated with increased short-term cardiovascular or limb events after accounting for comorbidities. These findings suggest that Lp(a)’s prognostic value may be limited in secondary prevention settings but could remain relevant for primary prevention and risk stratification. Further prospective studies are needed to assess the utility of Lp(a)-lowering therapies in PAD populations.
Lipoprotein(a) (Lp(a)) is a lipoprotein comprising an LDL-like particle attached to a highly glycosylated protein called apolipoprotein(a) (apo(a)). , Lp(a) is genetically determined through variations in the LPA gene. The LPA Kringle IV type 2 (KIV-2) repeat polymorphism is particularly significant, as it influences apolipoprotein(a) size and is inversely associated with circulating Lp(a) concentrations. Lp(a) concentrations are known to vary among racial and ethnic groups, with individuals of African and South Asian ancestry typically exhibiting higher median levels compared to those of White or East Asian descent.
Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) with proatherogenic, potentially prothrombotic, and proinflammatory characteristics. , Given that PAD represents an atherosclerotic disease process, a causal contribution from Lp(a) is biologically plausible. Increasing evidence links it with peripheral artery disease (PAD), a condition affecting over 200 million people globally. Clinically significant elevations in Lp(a), typically ≥50 mg/dL (approximately 125 nmol/L), impact about 20% of adults globally, positioning Lp(a) as one of the most common inherited risk factors for cardiovascular disease. Current major guidelines advocate for a 1-time Lp(a) measurement in everyone to help identify those at elevated cardiovascular risk. ,,
In light of these characteristics, therapeutic strategies targeting Lp(a) have gained interest, and understanding its association with PAD is of increasing clinical importance. Conflicting findings in the literature have raised questions about whether elevated Lp(a) simply reflects a higher burden of traditional cardiovascular risk factors or independently worsens short-term outcomes in PAD patients. This distinction holds significant clinical relevance, especially as novel antisense oligonucleotide therapies and small interfering RNA’s that target Lp(a) reduction enter late-stage trials. ,
However, these trials are largely centered on evaluating the risk of coronary artery disease and stroke and do not include PAD. Our study aims to clarify the prognostic significance of Lp(a) in PAD and inform ongoing efforts to personalize risk mitigation strategies in the era of emerging Lp(a)-lowering therapeutics.
Methods
We conducted a retrospective cohort study using the TriNetX Research Network. The study was conducted over a 15-year period, from January 1, 2010, to January 1, 2025. We identified adult patients (aged ≥18 years) with a diagnosis of PAD using validated ICD-9 and ICD-10 codes. Among them, patients with available Lp(a) measurements were stratified into 2 groups: those with elevated Lp(a), defined as >50 mg/dL, and those without elevated levels.
To minimize selection bias and confounding, we performed 1:1 propensity score matching using nearest-neighbor matching with a caliper of 0.1. Matching variables included age, sex, race, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease, smoking status, and prior stroke. The primary outcomes of interest were 1-year rates of myocardial infarction, stroke, major adverse cardiovascular events (MACE), all-cause mortality, and major adverse limb events (MALE). MACE was defined as a composite of myocardial infarction, stroke, or cardiovascular death, while MALE included events such as acute limb ischemia, major amputation, or need for peripheral revascularization.
Continuous variables were compared using independent sample t -tests. Categorical variables were analyzed using chi-square tests or Fisher’s exact tests, as appropriate. Kaplan–Meier survival analysis was conducted to compare mortality outcomes over time between groups. All statistical analyses were conducted using TriNetX, with a p-value of less than 0.05 considered statistically significant.
Results
Between January 1, 2010, and January 1, 2025, we identified 1,790,984 adults with PAD in the U.S. TriNetX network. Of these, 3,397 (0.2%) had elevated Lp(a) levels (≥50 mg/dL), while 1,787,587 had Lp(a) levels below this threshold. A 1:1 propensity score match generated 2 balanced cohorts of 3,397 patients each.
Before matching, the elevated Lp(a) group was older (mean age 68.2 ± 12.6 years vs 65.4 ± 16.3 years; p < 0.01) and had a significantly higher burden of cardiovascular comorbidities, including hypertension (80.9% vs 51.7%), coronary artery disease (50.6% vs 23.2%), diabetes mellitus (42.4% vs 27.5%), and heart failure (27.0% vs 14.1%) (all p < 0.01). We performed a 1:1 propensity score matching to mitigate confounding factors, resulting in a matched cohort of 3,397 patients in each group. After matching, there were no statistically significant differences in age, sex, or comorbidities between the 2 groups, confirming adequate balance across covariates ( Table 1 ).
Table 1
Baseline characteristics before and after matching
| Variable/Outcome | Matched PAD–Lp(a) | Matched PAD no Lp(a) | p-value |
|---|---|---|---|
| Baseline characteristics | |||
| Age (years) | 68.2 ± 12.6 | 67.9 ± 12.8 | 0.20 |
| Male (%) | 40.8 | 41.1 | 0.82 |
| Hypertension (%) | 80.9 | 81.0 | 0.97 |
| CAD (%) | 50.6 | 50.5 | 0.92 |
| Diabetes (%) | 41.2 | 41.9 | 0.68 |
| Hyperlipidemia (%) | 77.0 | 77.5 | 0.56 |
| Heart Failure (%) | 27.0 | 26.6 | 0.74 |
At 1-year follow-up in the unmatched cohort, PAD patients with elevated Lp(a) exhibited higher incidence rates of acute myocardial infarction (AMI) (7.9% vs 5.6%, p = 0.02), ischemic stroke (8.8% vs 6.7%, p < 0.01), and composite MACE (18.5% vs 16.3%, p = 0.01). Paradoxically, the same group demonstrated lower all-cause mortality (4.6% vs 7.2%, p < 0.01) and MALE (3.2% vs 5.6%, p < 0.01). This counterintuitive result may reflect survival bias or residual confounding. When outcomes were reassessed in the matched cohort, the observed differences were no longer statistically significant, suggesting that they may have been driven by confounding variables ( Table 2 , Table 3 ).
Table 2
One-year outcomes in propensity-matched PAD patients with vs without elevated Lp(a)
| Outcome | Elevated Lp(a) | Nonelevated Lp(a) | p-value |
|---|---|---|---|
| Acute myocardial infarction (%) | 7.9 | 7.4 | 0.42 |
| Ischemic stroke (%) | 8.8 | 8.5 | 0.56 |
| MACE (%) | 18.5 | 18.0 | 0.39 |
| All-cause mortality (%) | 4.6 | 4.9 | 0.48 |
| MALE (%) | 3.2 | 3.4 | 0.60 |
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